A Textbook of Clinical Pharmacology and Therapeutics

• pulmonary,

• pulmonary, retroperitoneal and pericardial fibrotic reactions have been associated with the ergot-derived dopamine agonists (bromocriptine, cabergoline, lisuride and pergolide). APOMORPHINE Apomorphine is a powerful dopamine agonist at both D1 and D2 receptors, and is used in patients with refractory motor oscillations (on–off phenomena). It is difficult to use, necessitating specialist input. The problems stem from its pharmacokinetics and from side effects of severe nausea and vomiting. The gastrointestinal side effects can be controlled with domperidone. Apomorphine is started in hospital after pretreatment with domperidone for at least three days, and withholding other antiparkinsonian treatment at night to provoke an ‘off’ attack. The subcutaneous dose is increased and when the individual dose requirement has been established, with reintroduction of other drugs if necessary, administration is sometimes changed from intermittent dosing to subcutaneous infusion via a syringe pump, with patient-activated extra boluses if needed. Apomorphine is extensively hepatically metabolized and is given parenterally. The mean plasma t1/2 is approximately 30 minutes. CATECHOL-O-METHYL TRANSFERASE INHIBITORS Use Tolcapone and entacapone are used for adjunctive therapy in patients who are already taking L-dopa/dopa decarboxylase inhibitor combinations with unsatisfactory control (e.g. end-ofdose deterioration). These agents improve symptoms with less on–off fluctuations, as well as reducing the levodopa dose requirement by 20–30%. Adverse effects arising from increased availability of L-dopa centrally can be minimized by decreasing the dose of levodopa combination treatment prospectively. Because of hepatotoxicity associated with tolcapone it is only used by specialists when entacapone is ineffective as an adjunctive treatment. Mechanism of action Reversible competitive inhibition of COMT, thereby reducing metabolism of L-dopa and increasing its availability within nigrostriatal nerve fibres. It is relatively specific for central nervous system (CNS) COMT, with little effect on the peripheral COMT, thus causing increased brain concentrations of L-dopa, while producing less of an increase in plasma concentration. Adverse effects These include the following: • nausea, vomiting, diarrhoea and constipation; • increased levodopa-related side effects; • neuroleptic malignant syndrome; • dizziness; • hepatitis – rare with entacapone, but potentially lifethreatening with tolcapone (liver function testing is mandatory before and during treatment); • urine discolouration. PARKINSON’S SYNDROME AND ITS TREATMENT 127 Pharmacokinetics Tolcapone is rapidly absorbed and is cleared by hepatic metabolism. At recommended doses it produces approximately 80–90% inhibition of central COMT. Drug interactions Apomorphine is metabolized by O-methylation, so interaction with COMT inhibitors is to be anticipated. COMT inhibitors should not be administered with MAOIs, as blockade of both pathways of monoamine metabolism simultaneously has the potential to enhance the effects of endogenous and exogenous amines and other drugs unpredictably. MONOAMINE OXIDASE INHIBITORS – TYPE B SELEGILINE AND RASAGILINE Use Initial small controlled studies in Parkinson’s disease reported that disease progression was slowed in patients treated with selegiline alone, delaying the need to start levodopa. Largerscale studies have not confirmed this conclusion. MAO type B inhibitors, such as selegiline and rasagiline, may be used in conjunction with levodopa to reduce end-of-dose deterioration. Mechanism of action There are two forms of monoamine oxidase (MAO), namely type A (substrates include 5-hydroxytryptamine and tyramine) and type B (substrates include phenylethylamine). MAO-B, is mainly localized in neuroglia. MAO-A metabolizes endogenous adrenaline, noradrenaline and 5-hydroxytryptamine, while the physiological role of MAO-B is unclear. Both isoenzymes metabolize dopamine. Inhibition of MAO-B raises brain dopamine levels without affecting other major transmitter amines. Because selegiline and rasagiline selectively inhibit MAO-B, they are much less likely to produce a hypertensive reaction with cheese or other sources of tyramine than non-selective MAOIs, such as phenelzine. Adverse effects Selegiline is generally well tolerated, but side effects include the following: • agitation and involuntary movements; • confusion, insomnia and hallucinations; • nausea, dry mouth, vertigo; • peptic ulceration. Pharmacokinetics Oral selegiline is well absorbed (100%), but is extensively metabolized by the liver, first to an active metabolite, desmethylselegiline (which also inhibits MAO-B) and then to amphetamine and metamphetamine. Its plasma t1/2 is long (approximately 39 h). Drug interactions At very high doses (six times the therapeutic dose), MAO-B selectivity is lost and pressor responses to tyramine are

128 MOVEMENT DISORDERS AND DEGENERATIVE CNS DISEASE potentiated. Hypertensive reactions to tyramine-containing products (e.g. cheese or yeast extract) have been described, but are rare. Amantadine and centrally active antimuscarinic agents potenti-ate the anti-parkinsonian effects of selegiline. Levodopa-induced postural hypotension may be potentiated. DRUGS AFFECTING THE CHOLINERGIC SYSTEM MUSCARINIC RECEPTOR ANTAGONISTS Use Muscarinic antagonists (e.g. trihexyphenidyl, benzatropine, orphenadrine, procyclidine) are effective in the treatment of parkinsonian tremor and – to a lesser extent – rigidity, but produce only a slight improvement in bradykinesia. They are usually given in divided doses, which are increased every two to five days until optimum benefit is achieved or until adverse effects occur. Their main use is in patients with parkinsonism caused by antipsychotic agents. Mechanism of action Non-selective muscarinic receptor antagonism is believed to restore, in part, the balance between dopaminergic/cholinergic pathways in the striatum. Key points Treatment of Parkinson’s disease • A combination of levodopa and a dopa-decarboxylase inhibitor (carbidopa or benserazide) or a dopamine agonist (e.g. ropinirole) are standard first-line therapies. • Dopamine agonists and COMT inhibitors (e.g. entacapone) are helpful as adjuvant drugs for patients with loss of effect at the end of the dose interval, and to reduce ‘on–off’ motor fluctuations. • The benefit of early treatment with an MAO-B inhibitor, selegiline, to retard disease progression is unproven, and it may even increase mortality. • Polypharmacy is almost inevitable in patients with longstanding disease. • Ultimately, disease progression requires increasing drug doses with a regrettable but inevitable increased incidence of side effects, especially involuntary movements and psychosis. • Anticholinergic drugs reduce tremor, but dose-limiting CNS side effects are common, especially in the elderly. These drugs are first-line treatment for parkinsonism caused by indicated (essential) antipsychotic drugs. Adverse effects These include the following: • dry mouth, blurred vision, constipation; • precipitation of glaucoma or urinary retention – they are therefore contraindicated in narrow angle glaucoma and in men with prostatic hypertrophy; • cognitive impairment, confusion, excitement or psychosis, especially in the elderly. Pharmacokinetics Table 21.1 lists some drugs of this type that are in common use, together with their major pharmacokinetic properties. SPASTICITY Table 21.1: Common muscarinic receptor antagonists, dosing and pharmacokinetics Spasticity is an increase in muscle tone, for example, due to damage to upper motor neurone pathways following stroke or in demyelinating disease. It can be painful and disabling. Treatment is seldom very effective. Physiotherapy, limited surgical release procedures or local injection of botulinum toxin (see below) all have a role to play. Drugs that reduce spasticity include diazepam, baclofen, tizanidine and dantrolene, but they have considerable limitations. Diazepam (see Chapter 18, Hypnotics and anxiolytics) facili-tates γ-aminobutyric acid (GABA) action. Although spasticity and flexor spasms may be diminished, sedating doses are often needed to produce this effect. Baclofen facilitates GABA-B receptors and also reduces spasticity. Less sedation is produced than by equi-effective doses of diazepam, but baclofen can cause vertigo, nausea and hypotension. Abrupt withdrawal may precipitate hyperactivity, convulsions and autonomic dysfunction. There is specialist interest in chronic administration of low doses of baclofen intrathecally via implanted intrathecal cannulae in selected patients in order to maximize efficacy without causing side effects. Dantrolene (a ryanodine receptor antagonist) is generally less useful for symptoms of spasticity than baclofen because muscle power is reduced as spasticity is relieved. It is used intravenously to treat malignant hyperthermia and the neuroleptic malignant syndrome, for both of which it is uniquely effective (see Chapter 24). Its adverse effects include: • drowsiness, vertigo, malaise, weakness and fatigue; • diarrhoea; • increased serum potassium levels. Drug Route of Half-life (hours) Metabolism and Special features administration excretion Trihexyphenidyl Oral 3–7 Hepatic Orphenadrine Oral 13.7–16.1 Hepatic-active Central metabolite stimulation Procyclidine Oral 12.6 Hepatic